Swollen joints cartilage degradation and bone deformation,
these are the symptoms of rheumatoid arthritis, an autoimmune disease in
which the joints are chronically inflamed. Accompanying these symptoms is a severe
unrelenting pain. A pain that increases in severity as the inflammation persists.
The joint is innervated by pain related sensory neurons or nociceptors. In the
arthritic joint they are bombarded with inflammatory factors. In response to
the irritation from this inflammatory soup, nociceptors fire nerve impulses to the central
nervous system where pain is consciously perceived. Over time nociceptors endings
become increasingly responsive to stimuli, a phenomenon known as peripheral sensitization.
A major player in peripheral sensitization is nerve growth factor or NGF. This trophic
factor triggers cells to release inflammatory mediators including histamine, bradykinin,
cytokines, protons and NGF itself. These mediators lead to the recruitment of immune
cells from the blood fueling the inflammatory response. As a result this lowers barriers to
nociceptors stimulation. Pain signals travel to the central nervous system and back to
the joint and surrounding tissues through collateral nerve branches. The signals induce
local release of substance P and calcitonin gene related peptide. These neuropeptides
contribute to the spread of inflammation further amplifying the pain. NGF also increases pain
sensation by acting directly on nociceptor endings. On the surface of the nocicpetor,
NGF binds to its cognate receptor tyrosine kinase track A. This interaction causes
track A to dimerize and auto phosphorylate forming binding sites for adapter proteins
coupled to several intracellular signaling cascades. In one of these signaling pathways,
trip v1 cation channels that open in response to noxious heat and acidity become phosphorylated.
This modification increases both channel density and activity of trip v1. Other ion channels also
become activated rendering the nociceptor membrane more susceptible to depolarization
due to a greater influx of cations. In addition to local changes, NGF also effects distant sites.
NGF track A complexes are taken up into the nociceptor forming signalling endosomes.
Through retrograde transport these endosomes are
moved to the cell body in the dorsal root ganglion.
Once there, the complex acts on transcription factors to induce
changes in gene expression. This leads to an increased production of pronociceptive molecules.
The expression of a number of ion channels is also increased including voltage-gated sodium channels,
acid sensing ion channels and trip v1. These ion channels
are transported to both peripheral and central ends of the nociceptor.
As a result of heightened ion channel, pain mediator and neuropeptide activity,
there is greater activation of nociceptive pathways and ultimately greater pain sensation.
Learning how NGF drives inflammation and pain sensitization is fundamental
to the development of therapeutic drugs, drugs that can improve pain management for
people suffering from rheumatoid arthritis. Currently, researchers at McGill University
are working towards an understanding of the maturation and degradation pathways
of NGF in inflamed joints. By manipulating the enzymes responsible for NGF production,
they hope to develop pharmacological interventions to reduce levels of endogenous
NGF. A research area with great therapeutic potential that remains largely unexplored.